Male Fischer-344 rats administered a single intraperitoneal dose of perfluoro-n-octanoic acid (PFOA) or perfluoro-n-decanoic acid (PFDA) display a similar "wasting toxicity" characteristic of perfluorocarboxylic acids, with marked differences in temporal expression. Food/water consumption and urine output were monitored daily in PFOA-treated, PFDA-treated, and control rats. Fluorine-19 nuclear magnetic resonance (NMR) spectroscopy was used to monitor these fluorocarbons and possible fluoro metabolites in vivo, and to correlate differences in elimination with differences in effective toxicity. The data reveal a prolonged hypophagic response to PFDA and a more acute but transient response associated with PFOA treatment. PFOA causes a greater decline in food consumption than PFDA within the first 24 h postdose. PFOA-treated rats also show a ca. 2.5-fold increase in urine output on day 1, with only a slight increase in water consumption. In contrast to PFDA, PFOA-treated rats recover from hypophagia within 8 days. Fluorine-19 NMR spectra of various bodily fluids and liver in vivo display resonances of the parent PFOA or PFDA compounds and do not reveal any evidence of metabolism. Inorganic fluoride from dietary sources is detected in urine from both exposed and control rats. Differences in the route of excretion of PFOA vs PFDA are apparent from the spectral signal-to-noise ratio. The data suggest that PFOA is more readily excreted in the urine while PFDA is preferentially carried in bile. These apparent differences in elimination may account for their observed differences in effective toxicity. The acute transient toxicity and higher LD50 associated with PFOA may result from its rapid renal clearance.(ABSTRACT TRUNCATED AT 250 WORDS)
Noncancer risk assessment traditionally relies on applied dose measures, such as concentration in inhaled air or in drinking water, to characterize no-effect levels or low-effect levels in animal experiments. Safety factors are then incorporated to address the uncertainties associated with extrapolating across species, dose levels, and routes of exposure, as well as to account for the potential impact of variability of human response. A risk assessment for chloropentafluorobenzene (CPFB) was performed in which a physiologically based pharmacokinetic model was employed to calculate an internal measure of effective tissue dose appropriate to each toxic endpoint. The model accurately describes the kinetics of CPFB in both rodents and primates. The model calculations of internal dose at the no-effect and low-effect levels in animals were compared with those calculated for potential human exposure scenarios. These calculations were then used in place of default interspecies and route-to-route safety factors to determine safe human exposure conditions. Estimates of the impact of model parameter uncertainty, as estimated by a Monte Carlo technique, also were incorporated into the assessment. The approach used for CPFB is recommended as a general methodology for noncancer risk assessment whenever the necessary pharmacokinetic data can be obtained.
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